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EP-3704101-B1 - COCRYSTALS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF TREATMENT INVOLVING SAME

EP3704101B1EP 3704101 B1EP3704101 B1EP 3704101B1EP-3704101-B1

Inventors

  • LANE, BENJAMIN, S.
  • GU, CHONG-HUI

Dates

Publication Date
20260506
Application Date
20181102

Claims (16)

  1. A cocrystal comprising a compound of formula (I) and citric acid.
  2. The cocrystal of claim 1, wherein the cocrystal is characterized by an X-ray powder diffraction pattern, acquired in reflection mode, comprising: (i) at least one peak position, in degrees 2-theta (±0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0; and/or: (ii) at least two peak positions, in degrees 2-theta (±0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0; and/or: (iii) at least three peak positions, in degrees 2-theta (±0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0; and/or: (iv) at least four peak positions, in degrees 2-theta (±0.2 degrees 2-theta), selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0; and/or: (v) peak positions, in degrees 2-theta (±0.2 degrees 2-theta), of 5.7 and 8.4, and at least three peak positions selected from the group consisting of 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0.
  3. The cocrystal of claim 1 or 2, wherein the cocrystal is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 170.6 °C (±2.0 °C).
  4. The cocrystal of any one of claims 1-3, further comprising water, optionally wherein the compound of formula (I), citric acid, and water are present in a molar ratio of 2:1:1; and/or optionally wherein the cocrystal comprises four molecules of the compound of formula (I), two citric acid molecules, and two water molecules per unit cell.
  5. A pharmaceutical composition comprising a therapeutically effective amount of the cocrystal of any one of claims 1-4 and one or more pharmaceutical excipients.
  6. A cocrystal of any one of claims 1-4 or a pharmaceutical composition of claim 5 for use in treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof.
  7. The cocrystal or pharmaceutical composition of claim 6, wherein the cancer is characterized by the presence of an IDH1 mutation; optionally wherein the IDH1 mutation is an R132X mutation.
  8. The cocrystal or pharmaceutical composition of claim 7, wherein the IDH1 mutation is an R132H or R132C mutation.
  9. The cocrystal or pharmaceutical composition of claim 6, wherein the cancer is characterized by the presence of an IDH2 mutation, optionally wherein the IDH2 mutation is an R140X mutation or an R172X mutation.
  10. The cocrystal or pharmaceutical composition of claim 9, wherein the IDH2 mutation is an R140Q, R140W, or R140L mutation.
  11. The cocrystal or pharmaceutical composition of claim 9, wherein the IDH2 mutation is an R172K or R172G mutation.
  12. The cocrystal or pharmaceutical composition of any one of claims 7-11, wherein the IDH1 mutation or the IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.
  13. The cocrystal or pharmaceutical composition of any one of claims 6-12, wherein the cancer is selected from glioma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL); optionally wherein the cancer is glioma.
  14. The cocrystal or pharmaceutical composition of claim 13, wherein the glioma is a low grade glioma or a secondary high grade glioma, optionally wherein the glioma is a secondary high grade glioma, and the secondary high grade glioma is glioblastoma.
  15. The cocrystal or pharmaceutical composition of any one of claims 6-14, wherein the cancer is refractory or relapsed.
  16. The cocrystal or pharmaceutical composition of any one of claims 6-14, wherein the cancer is newly diagnosed or previously untreated.

Description

BACKGROUND Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM_005896.2 and NP_005887.2 respectively. The nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al., Submitted (DEC-2008) to UniProtKB; Kullmann et al., Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006). Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate. It has been discovered that mutations of IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44). IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively. The nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al., Submitted (NOV-1992) to the EMBL/GenBank/DDBJ databases; and The MGC Project Team, Genome Res. 14:2121-2127(2004). Non-mutant, e.g., wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). It has been discovered that mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44). U.S. Publication No. 2015/0018328 A1 discloses a compound described by the chemical name 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, which has been shown to act as an inhibitor of mutant IDH1 and IDH2 proteins in biochemical and cellular assays. The compound of formula (I) in free form is disclosed in WO2015003640. SUMMARY The present disclosure relates to solid forms (e.g., cocrystals and other crystalline forms) of a compound of formula (I) In one aspect, the disclosure relates to a cocrystal comprising the compound of formula (I) and citric acid. In another aspect, the disclosure relates to a cocrystal comprising the compound of formula (I) and maleic acid. In other aspects, the disclosure relates to crystalline forms of the free compound of formula (I). In other aspects, the disclosure relates to a drug substance comprising a solid form of the compound of formula (I). In other aspects, the disclosure relates to methods of preparing solid forms of the compound of formula (I). In another aspect, the present application relates to a pharmaceutical composition comprising a solid form of the compound of formula (I) and one or more pharmaceutical excipients. In another aspect, the present application relates to a method of treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need there